Shape Of Survival Curve Research Articles

The intrinsic radiosensitivity of lymphocytes in chronic lymphocytic leukaemia, quantitatively determined independently of cell death rate factors.

Survival curve shape for lymphocytes X-irradiated in vitro is governed by death rate as well as intrinsic radiosensitivity. We have resolved into these two components the survival curves obtained for CLL lymphocytes by use of a simple mathematical model. A multiple correlation coefficient comparing the predicted with the experimental survival curves was close to unity (0.954-0.999). For 14/18 patients with unequivocal B-cell CLL, the leukaemic (colchicine ultrasensitive) cells behaved as a homogeneous population (D37 0.32-1.28 Gy). This is similar to the more radiosensitive class of lymphocytes of normal blood (believed to include the B cells) and is some 4-fold less than the more radioresistant class (comprising most of the T cells). The lethally hit cells were homogeneous in death rate, which followed first order kinetics. The half-life (range 9-87 h) was, on average, some 50 per cent shorter than the more radiosensitive normal lymphocytes. The remaining four patients constituted a miscellaneous group. From one of these, it can be seen that an excessively slow death rate can give the misleading impression of radioresistance. It is hypothesized that the benefit afforded certain CLL patients treated with low-dose total body irradiation (TBI) or splenic irradiation (SI) may reside, partly, in the sparing of T lymphocytes of the helper type and in accompanying selective elimination (or functional inactivation) of those of the suppressor type.

Two types of lethal damage induced by pepleomycin in cultured Chinese hamster V79 cells.

The cytotoxic effect of pepleomycin (PEP), a derivative of bleomycin (BLM), was investigated and compared with that of BLM on cultured Chinese hamster V79 cells. The concentration-response curve of PEP was biphasic, like that of BLM: the D0 values of the first and second slopes for PEP were 32 micrograms/ml and 140 micrograms/ml, while those of BLM were 60 micrograms/ml and 140 micrograms/ml, respectively. The ratios of D0 for BLM to that for PEP were 1.88 for the first slope and 1.0 for the second one, suggesting that PEP is more cytotoxic than BLM on a unit concentration basis. The time-response curve for PEP showed that the surviving fraction dropped immediately, then rose gradually and finally declined slowly. Analysis of these curves together with the results of further experiments suggested the induction of two types of lethal damage by PEP; potentially lethal damage and non-reparable lethal damage. Potentially lethal damage was induced by PEP treatment, developed within a few minutes, was fixed as lethal damage by trypsinization and was repaired fully within 1 hr if trypsinization was not applied. Non-reparable lethal damage was another type of damage induced by PEP and led to cell death without repair. The two types of lethal damage can account for not only the various shapes of survival curves, but also the differences in cytotoxicity of PEP and BLM.

Implications of tissue target-cell survival-curve shape for values of split-dose recovery doses: late versus early effects.

Recent data from this laboratory on split-dose recovery for early and late effects in pig skin are consistent with the linear-quadratic model for cell survival, and with relative cell survival-curve shapes for early- and late-effect target cells where the early-effect cells have an initially steeper and straighter survival-curve than the late-effect cells.

Is there a relationship between hypoxia, contact resistance, and intercellular communication?

This investigation addresses the shape of radiation survival curves of cells cultured as multicell spheroids. It is shown that spheroids of cells capable of intercellular communication by gap-junctions display survival curves lacking a radioresistant fraction of hypoxic cells. Compared to the corresponding monolayers, these spheroid survival curves exhibit a uniform increase in radioresistance due to the "contact effect". In contrast, biphasic survival curves indicative of hypoxic cells are obtained with non-communicating spheroids, however, without indication of a contact effect. Evidence is presented that this relationship between intercellular communication, hypoxia, and contact effect may possibly also hold for survival curves of solid tumors.

On competitive failure modes and the usefulness of a "survival curve point of view".

A number of medical phenomena may be discussed in terms of the probability of something “surviving” as a function of time, dose, distance, etc. Employing elementary results of engineering reliability theory, we examine the different shapes of survival curves which can arise when several modes of failure compete for the members of a homogeneous or heterogeneous population. A variety of examples of medical interest illustrate the approach.

Topographic variations in the clonogenic response of intestinal crypts to cytotoxic treatments.

In the intestinal crypt microcolony assay, a "surviving fraction" of whole crypts is calculated conventionally by dividing the number of regenerating crypts three to four days after treatment by the number of crypts in untreated animals, both measured around a complete intestinal circumference in transverse sections of gut. We show that in relation to the mesenteric attachment of the gut, crypts in different regions of this circumference differ in their survival characteristics after radiation or mechlorethamine hydrochloride ("HN2"). Crypts associated with Peyer's patches are resistant to both agents (large initial shoulder, shallow slope). The mode of administration of HN2 (IP vs. IV) influences the shape of the crypt survival curve. Differences in size of shoulder and slope affect the estimate of numbers of microcolony-forming cells per crypt (A). For radiation, this number can vary sevenfold, depending on the region of circumference chosen for analysis. Different agents of assay result in radically different values for A.

The influence of the 'collection injury' on the survival and distribution of indium-111-labeled canine platelets.

The extent of the 'collection injury' sustained by platelets during labelling with In-111-oxine was investigated in three matched pairs of beagle dogs. The influence of the procedure on the survival, kinetics, in vivo distribution and fate of the labelled platelets was determined by serial blood sampling and quantitative computerized scintillation camera studies. Injured labelled platelets were removed in the matched dog acting as a biological filter. The survival, distribution and fate of the 'filtered' and 'unfiltered' platelets were compared. The mean platelet lifespan of the 'filtered' and 'unfiltered' platelets did not differ significantly, but the shape of the survival curve of the filtered platelets fitted a linear function more closely than that of the unfiltered platelets. Radioactivity in the different organs and regions was serially quantitated and expressed as a percentage of whole body radioactivity. Splenic and hepatic radioactivity of filtered and unfiltered platelets did not differ significantly at equilibrium or at the end of platelet lifespan. It is concluded that the currently employed isolation and labelling techniques for platelets are suitable for quantitative in vivo studies with a computerized scintillation camera system. The shape of platelet survival curves should, however, be interpreted with some caution as it may be influenced by these procedures.

A model describing microbial inactivation and growth kinetics

A model based on the chance of collision between environmental water molecules having appropriate energy and microbial cells, and leading to description of both inactivation and growth kinetics is presented. Functions derived from the model can describe the known shapes of survival curves (concave, convex, sigmoid, linear, on semi-log plot), the tailing-off phenomenon, some prominent behaviour of growing population kinetics, and are provided with fair predictive power. The main features of the model as heat inactivation is concerned are: (1) always the survival curves are expected to be concave on semi-log plot, unless some lag occurs in reaching the treatment temperature; (2) the tailing-off occurs when the concentration of living cells and/or water molecules having lethal energy is low enough; (3) heat inactivation curve at any temperature and whichever is the water content of the medium can easily be predicted, provided a single survivor concentration after time t at temperature T in a medium of defined composition is known; (4) the energy value of molecules leading to inactivation is about half the activation energy expected from classical thermodynamic treatment of reaction rate; (5) the concentration of water molecules having enough energy to drive the process changes exactly Q 10 times each 10 °C or ten times each z degrees. As radiation or chemical inactivation is concerned the model allows the description of known shapes of survival curves, linking the shape of the survival curve to the concentration of specific cellular molecular groups. Appropriate modification of the fundamental equation of the model leads to description of cell growth kinetics as a function of cell concentration, temperature, water content in the environment, the presence of metabolic by-products, antimetabolites, etc., as well as to the formulation of hypotheses about growth, death and senescence regulating structures.

The Effect of Irradiated Feeder Cells on the X-Ray Survival Curve Shape of Freshly Explanted Human Tumor Cells and a Standard Human Tumor Cell Line

Curves for the survival of reproductive capacity in vitro were obtained for freshly explanted human tumor cells and the standard human tumor cell line HeLa ${\rm S}\text{-}3_{{\rm oxf}}$ following X irradiation. The results suggest that preirradiated feeder cells have a more significant effect at doses of about 700-900 rad (in terms of increased survival of an initially viable irradiated test cell population) than effective feeder cells produced in the test cell population. A direct effect of using irradiated feeder cells is an increase in the size of the shoulder as measured by $D_{{\rm q}}$ and an increase in the gradient of the high-dose region of the survival curve.

Response of cultured 9l cells to spirohydantoin mustard and x-rays

Rat brain tumor cells (9L) were treated in vitro for 1 hr with 2 μg/ml (∼30% survival) of spirohydantoin mustard (SHM) 4 and 24 hr before, during, and 4 and 24 hr after graded doses of radiation (0–20 Gy). The resulting survival curves generated from colony formation data and corrected for drug kill indicate that for all schedules SHM enhanced the radiation response, particularly for surviving fractions greater than 0.5. Analysis of the combination data using isobolograms indicates the effects of the separate agents were additive in producing either 1, 2, or 3 log cell kills. Therefore, the enhancement of the radiation response by SHM can be explained solely on the basis of the shapes of the single agent survival curves.

NSD and cell survival.

The relation between the NSD concept and cell survival in fractionated irradiation is established; the slope of Strandquist's lines is related to the shape of survival curves for the given type of cells and radiation. A new parameter, CBE, derived from TDF for determining cumulative biological effect is proposed.

Isolation of Micrococcus radiodurans occurring in radurized sawdust culture media of mushroom.

Radio-resistant red pigmented micrococci were propagated from radurized sawdust culture media of mushroom subjected to from 1.0 to 2.0 Mrad and stored for one month at 20°C. Three strains, H 48, H 54 and H 55, were isolated from different samples of sawdust media. Many of the characteristics of strains H 54 and H 55 were the same as those of Micrococcus radiodurans R1 isolated by Anderson et al. On the contrary, strain H 48 had some distinct characteristics such as small cell size, nitrate-reducing property, requirement of riboflavin with thiamine for growth and salt-torelance. The GC content of the DNA of these strains ranged from 65 to 67 moles %, and their cell wall peptidglycan contained ornithine type subunit to warrant their description as the species of Micrococcus radiodurans.The resistances to gamma-radiation of these isolates were the same as that of strain R1. However, the shape of survival curves differed among the strains. The curves of H 54 and H 55 were sigmoidal like that of strain R1, but...

Changes in uv-Inactivation Kinetics and Division Delay in Schizosaccharomyces pombe Strains during Different Growth Phases

Logarithmic and stationary phase cultures of the wild type and a number of radiation-sensitive mutants of Schizosaccharomyces pombe were uv-irradiated and their survival curves as well as postirradiation division delay were studied. The mutants could be classified into two groups. One group showed a marked difference in the level of resistance as well as in the shape of survival curves due to a change in growth phase, while in the other group this difference was negligible. This differential response was found to to be related to a variation in uv-induced division delay in the mutants in different phases of growth. The implication of division delay on cell survival and shapes of survival curves is discussed in relation to a recently proposed model of cellular inactivation.

Fractionated dose radiotherapy and its relationship to survival curve shape

Summary The radiobiology fundamental to rational radiotherapy is a developing, enlarging subject. This was emphasized once again by the 6th L. H. Gray Conference (London, 16–20 September 1974); a Conference addressed to the relevance of the initial part of the clonogenic and/or stem cell survival curves to the total doses and fractionation regimens required for effective radiotherapy. To indicate why the conferees focused on the initial shape of the single-cell survival curve, the essential biophysics and cell biology are reviewed from which important implications for radiotherapy can be derived. The data presented at the Conference are summarized and make it clear that generalizations relative to survival curve shape are not possible. In addition, examples are developed indicating where and how other factors may be critical to the effectiveness of fractionation. Although definitive answers were few, the 6th L. H. Gray Conference served to identify a number of points of growth needed to improve the applicability of radiobiology to radiotherapy.

Cellular repair after X or gamma irradiation determined for several “gross” criteria on animals and patients

The shape of survival curves for several mammalian cell types has been studied by assessing the “recovered dose” (early recovery) for different sizes of the fractions. The following “gross” end-points have been used: skin reactions and intestinal death in mice, tumour regression, gross skin and mucosal reactions in patients. The increase of dose necessary to attain the chosen biological effect has been determined when a single irradiation dose D s is split into two equal doses 2 D i or when N fractions ( N × D s ) are “split” into 2 N equal “subfractions” ( N × 2 D i ); i is the interval between the two “subfractions” D i and the overall treatment time is kept constant. From the data obtained conclusions are drawn about the shape of cell survival curves in the low dose region and some implications for fast neutron therapy are discussed.

Concentrations of inoculated cells and shapes of survival curves.

Concentrations of inoculated cells and shapes of survival curves.

Protection of normal, lysogenic, and pyocinogenic strains against ultraviolet radiation by bound acriflavine.

The presence of bound acriflavine protects bacteria against the lethal effects of ultraviolet (UV) light, presumably because pyrimidine dimer formation is inhibited. Although acriflavine present in plating medium usually results in reduced viable counts from irradiated bacteria, no enhancement of lethal effects is observed when acriflavine is added to irradiated bacteria left in suspending buffer for 45 min before plating. Acriflavine remaining bound to the deoxyribonucleic acid of irradiated bacteria at the time they are plated likewise does not affect their survival. Protection is precisely dose-modifying unless some killing of bacteria by UV results from induction of prophage, against which bound acriflavine is less protective, or from induction of pyocin, against which there is no protection at all. It is inferred that prophage induction proceeds in part, and pyocin induction wholly, by virtue of effects of UV other than pyrimidine dimerization. The response of Escherichia coli strain B to radiation has been postulated to be attributable in part to induction of a prophage or a lethal protein; but exact dose modification was observed for this strain, to about the same extent, whether or not the irradiated organisms were grown in conditions thought to enhance the expected contribution to killing if such a mechanism were involved. Our results support the hypothesis that the inhibition by acriflavine of dimer formation is attributable to energy transfer mechanisms. They fail to support the hypothesis that shapes of survival curves (in particular the manifestation of "shoulders") can be attributed to inactivation by radiation of repair enzymes.

Recovery from sub-lethal damage by hypoxic tumour cells in vivo.

Abstract A method has been developed whereby the survival of tumour cells irradiated in vivo can be measured in terms of their colony forming ability in vitro. Using this technique, survival curves have been constructed for tumours irradiated in various conditions of oxygenation. When tumours were exposed to two equal doses of radiation separated in time, cells were able to recover from their sub-lethal damage. The doses chosen were such that the ratio of surviving cells that were hypoxic at the time of the first dose of radiation to those that were well-oxygenated was at least 20 to 1. A consideration of the shapes of survival curves showed that not only were these hypoxic cells capable of recovery from sub-lethal damage, but they remained hypoxic for the time during which this process took place. The survival curve for cells from tumours exposed to a first dose of 1,000 rads and graded second doses five hours later confirmed this deduction.

Changes in sensitivity of cells during exposure to radiation at low dose-rate.

SummaryA large sparing effect was observed for Chlamydomonas reinhardii when dose-rate was reduced. Cells given radiation at low dose-rate were subsequently given series of graded doses at a high dose-rate. Values of D0 were larger, and extrapolation numbers lower for survival curves at high dose-rate, following low dose-rate pre-treatment, than if no pre-treatment had been given. The processes which led to a change in sensitivity of cells, and lower extrapolation numbers for survival curves at high dose-rate following low dose-rate pre-treatment, may have contributed to the overall sparing effect of a reduction in dose-rate. Because the shape of the split-dose survival curve at high dose-rate was different from that of the single-dose survival curve, current models, which relate changes in shapes of survival curves as dose-rate is reduced to recovery of cells from sublethal damage, could not be applied.

Theory of radiation dose-survival curves for the case where organism lethality is defined as loss of reproductive capacity

Loss of reproductive capacity is the lethal mechanism most sensitive to radiation, and consequently the controlling mechanism of the dose-survival curve, for a wide range of organisms. A simple model of an organism consistent with this fact is used with two postulates concerning the statistical nature of the radiation damage to develop a general expression for the dose-survival curve controlled by this mechanism. The analysis leads to a number of deductions concerning the shape of survival curves and indicates how the radiation sensitivity may be considered as the product of two terms; one dependent on the organism alone and the other on the type of radiation. The general formula is expanded in terms of poisson distributions to give an expression which should be applicable to cells. A number of tables are included to illustrate this case numerically.